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Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a protein that in humans is encoded by the MALT1 gene. MALT1 is part of the paracaspase family and shows proteolytic activity. Since many of the substrates are involved in regulation of inflammatory responses, the protease activity of MALT1 has emerged as an interesting therapeutic target.

Background

An overview of MALT1

Mucosa-associated lymphoid lymphoma translocation protein 1 (MALT1), encoded by MALT1 gene, belongs to the paracaspase family. MALT1 has great influence on immunity, inflammation and lymphoid malignances by activating immune cells. NF-κB signaling pathway is controlled by MALT1, promoting the activation, proliferation and survival of the activated immune cells. In the past, MALT1 was regarded as an assembly platform for other signaling proteins, like T cell receptor signaling. However, the finding that MALT1 could induce proteotytic activity changes this view, and makes MALT1 a potential target in autoimmunity and cancer.

Inhibition of MALT1

The research for MALT1 inhibitors is encouraged by MALT1’s enzymatic activity in various biology processes. Z-VRPR-fmk, the first MALT1 inhibitor, exerts function by blocking MALT1 protease activity, resulting in inhibition of T-cell activation and IL-2 secretion. Recent studies have found it possible to develop MALT1 inhibitors in vivo since two types of MALT1 inhibitors have beendiscovered in high throughput screening approaches. Nagel et al reported three phenothiazine derivatives as MALT1 inhibitors with high specificity. Fontan identified a selective MALT1 inhibitor, MI-2, which binds to the active site of MALT1. MALT1 inhibitors play an essential role in immunomodulation and the treatment of lymphomas. The first MALT1 inhibitor, z-VRPR-fmk, has a preferential cytotoxicity on diffuse large B-cell lymphoma (DLBCL). The experiments in mice revealed that the compound MI-2 could prevent the growth of DLBCL. There are two reports about the MALT1 probes that are able to measure patients’ response to MALT1 inhibitors.

MALT1 and diseases

The function of MALT1 indicted an important role of MALT1 in the activate B cell–DLBCL, MALT lymphoma, and inflammatory diseases. For example, MALT1 could be detected in advanced stages of MALT1 for the linkage to oncogenic protein encoded by a chromosomal translocation. In the future, research on MALT1 will focus more on its molecular function and figure out the full spectrum of its substrates.

3. Mcallisterlucas, L. M., Baens, M. & Lucas, P. C. MALT1 protease: a new therapeutic target in B-lymphoma and beyond? Clinical Cancer Research An Official Journal of the American Association for Cancer Research 17, 6623 (2011).